The regulation of heart rate in response to stress, activity, and other stimuli is essential for mammalian survival. While each independent heart muscle has an inherent faculty for independent excitation, the heartbeat is initiated in a specialized group of muscle cells in the sinoatrial node of the heart, which form the pacemaker. The heart is also innervated by nerves that regulate the beat. When these nerves are active, they liberate chemicals such as noradrenaline or acetylcholine from their terminals, and these neurotransmitters affect the cardiac muscles directly. The pacemaker is inhibited by acetylcholine and excited by noradrenaline.
The release of acetylcholine (ACh) opens a K+ channel in the atrium, slowing the rate of depolarization that leads to initiation of the action potential.
This effect is mediated through a G-protein signal transduction pathway, involving a pertussis toxin-sensitive, heterotrimeric G-protein, Gk, probably belonging to the Gi/Go family. Activation of the K+ channel by Gk does not require cytoplasmic intermediates, suggesting direct coupling of one or more G-protein subunits to the channel. However, a long-standing controversy exists as to which subunit couples to the channel. Both purified βγ subunit complex and α subunits of the Gi/Go family activate the channel in cell free, inside-out patches of atrial myocytes. Activation by the α subunits occurs at lower concentrations than that by βγ, but seems to be less efficient. The relative physiological importance of each pathway, as well as of possible involvement of the arachidonic acid pathway, is unclear.
A similar K+ channel is activated in the atrium by adenosine, ATP and epinephrine, probably also via a G-protein pathway. Furthermore, in nerve cells various 7-helix receptors, such as serotonin 5HT1A, ∂-opioid, GABAB and somatostatin couple to similar K+ channels, probably through direct activation by G-proteins. The similarity of the channels and signaling pathways in atrium and nerve cells is also shown by the coupling of a neuronal 5HT1A receptor (5HT1A-R) to the atrial channel, through transient expression in myocytes.
By electrophysiological and pharmacological criteria, these K+ channels belongs to a family of inward rectifiers that conduct K+ much better in the inward than the outward direction, are blocked by extracellular Cs+ and Ba2+, and are believed to possess a single-file pore with several permeant and blocking ion binding sites. Recently, the primary structures of two mammalian inward rectifier channels have been elucidated by cDNA cloning: an ATP-regulated K+ channel from kidney, and an inward rectifier from a macrophage cell line. Both appear to belong to a new superfamily of K+ channels, with only two transmembrane domains per subunit and a pore region homologous to that of K+, Ca2+ and Na+ voltage-dependent channels.
G-protein regulated K+ channels are important for the regulation of heart and nerve function. Determination of their molecular structure and regulation is therefore of great interest. Cloning of the channel protein genes and expression in a heterologous system would allow a molecular approach to investigation and manipulation of these regulatory pathways.
Relevant Literature
The activation of atrial K+ channels by G-proteins is reviewed in Kurachi et al. (1992) Prog. Neurobiol. 39:229–246; and Brown and Birnbaumer (1990) A. Rev. Physiol. 52:197–213. Logothetis et al. (1987) Nature 325:321–326 and Kurachi et al. (1989) Pflugers Arch. 413:325–327 provide evidence for activation by the βγ subunits. Codina et al. (1987) Science 236:442–445 show activation by the α-subunit. Karschin et al. (1991) P.N.A.S. 88:5694–5698 demonstrates the coupling of a neuronal receptor to the atrial K+ chanel.
Physiological characterization of the atrial K+ channels is reviewed by Hille, B. (1992) Ionic Channels of Excitable Membranes, 2nd edition (Sinauer, Sunderland, Mass.). The role of Mg2+ in blocking K+ efflux is discussed in Horie and Irisawa (1987) Am. J. Physiol. 253:H210–H214.
The sequence characterization of a mammalian inward rectifier K+ channel is disclosed in Ho et al. (1993) Nature 362:31–38; and Kubo et al. (1993) Nature 362:127–132. A brief review of these inward rectifying K+ channels may be found in Aldrich (1993) Nature 362:107–108.